title: C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome.
abstract: BACKGROUND
  Sensenbrenner syndrome is a heterogeneous ciliopathy that is characterised by skeletal and ectodermal anomalies, accompanied by chronic renal failure, heart defects, liver fibrosis and other features.
  
  
  OBJECTIVE
  To identify an additional causative gene in Sensenbrenner syndrome.
  
  
  METHODS
  Single nucleotide polymorphism array analysis and standard sequencing techniques were applied to identify the causative gene. The effect of the identified mutation on protein translation was determined by western blot analysis. Antibodies against intraflagellar transport (IFT) proteins were used in ciliated fibroblast cell lines to investigate the molecular consequences of the mutation on ciliary transport.
  
  
  RESULTS
  Homozygosity mapping and positional candidate gene sequence analysis were performed in two siblings with Sensenbrenner syndrome of a consanguineous Moroccan family. In both siblings, a homozygous mutation in the initiation codon of C14ORF179 was identified. C14ORF179 encodes IFT43, a subunit of the IFT complex A (IFT-A) machinery of primary cilia. Western blots showed that the mutation disturbs translation of IFT43, inducing the initiation of translation of a shorter protein product from a downstream ATG. The IFT-A protein complex is implicated in retrograde ciliary transport along axonemal microtubules. It was shown that in fibroblasts of one of the siblings affected by Sensenbrenner syndrome, disruption of IFT43 disturbs this transport from the ciliary tip to its base. As anterograde transport in the opposite direction apparently remains functional, the IFT complex B proteins accumulate in the ciliary tip. Interestingly, similar results were obtained using fibroblasts from a patient with Sensenbrenner syndrome with mutations in WDR35/IFT121, encoding another IFT-A subunit.
  
  
  CONCLUSIONS
  The results indicate that Sensenbrenner syndrome is caused by disrupted IFT-A-mediated retrograde ciliary transport.
authors.affiliation: Department of Human Genetics (855), Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands. h.arts@antrg.umcn.nl
authors.forename: Heleen H
authors.initials: HH
authors.lastname: Arts
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.forename: Dorus A
authors.initials: DA
authors.lastname: Mans
authors.forename: Sylvia E C
authors.initials: SE
authors.lastname: van Beersum
authors.forename: Machteld M
authors.initials: MM
authors.lastname: Oud
authors.forename: Emine
authors.initials: E
authors.lastname: Bolat
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Spruijt
authors.forename: Elisabeth A M
authors.initials: EA
authors.lastname: Cornelissen
authors.forename: Janneke H M
authors.initials: JH
authors.lastname: Schuurs-Hoeijmakers
authors.forename: Nicole
authors.initials: N
authors.lastname: de Leeuw
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Nine V A M
authors.initials: NV
authors.lastname: Knoers
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
mesh_terms: D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002923:Cilia / Q000235:genetics / Q000378:metabolism*; D019465:Craniofacial Abnormalities / Q000208:ethnology / Q000235:genetics*; D004476:Ectodermal Dysplasia / Q000208:ethnology / Q000235:genetics*; D005347:Fibroblasts / Q000502:physiology; D005407:Flagella / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009018:Morocco / Q000208:ethnology; D009154:Mutation; D009426:Netherlands / Q000453:epidemiology; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics* / Q000378:metabolism; D035781:Siblings; D013577:Syndrome; D014162:Transfection
chemical_list: D002352:Carrier Proteins; C561297:IFT43 protein, human; D011994:Recombinant Proteins